The role of natural killer(NK) and other natural cytotoxic effector cells in regulating virus infections will be examined. Model systems will be mice infected with mouse cytomegalovirus(MCMV), lymphocytic choriomeningitis virus(LCMV), and mouse hepatitis virus(MHV). Using microcytotoxicity assays and leukocyte fractionation schemes, the effector cells mediating "natural" cytotoxicity against virus-infected cultured cells will be identified under conditions that discriminate between NK cells, natural cytotoxic(NC) cells, a newly described virus-killer(VK) cell, and cytotoxic macrophages. Similarly, cytotoxicity in vivo will be examined by injecting mice intravenously and by other routes with 125 iododeoxyuridine-labeled virus-infected cells and determining the loss of radioactivity in vivo. Leukocytes will be transferred into such mice after immunosuppression to identify the effector system mediating the cytotoxicity. A major technique to distinguish NK mechanisms from other mechanisms in this and other systems will be to inject mice (or treat leukocytes in culture) with antibody to asialo GM1, which selectively depletes NK cell activity while leaving other known effector systems intact. Using this and other immune reagents, the effects of NK cells on virus titers, pathology, mortality, and immunosuppression during acute and persistent virus infections in vivo will be delineated. The progression of MCMV, LCMV, and MHV in NK cell-depleted mice will be examined, and attempts will be made to reconstitute their resistance by transfer of purified NK cells and NK clones. The effects of NK cells under conditions of interferon or antiviral antibody treatment will be similarly examined in virus-infected mice. The possibility that virus-infected cells may chemotactically attract NK cells will also be tested. Our recent data indicate that natural cytotoxic cells may play major roles in limiting virus infections, but several effector systems may be involved, and different systems may vary in importance with injection route and target organ. Understanding such cytotoxic mechanisms would be of use in preventing or limiting virus infections in man.